We are studying the secretin-VIP family of G-protein coupled receptors. These receptors have virtually no amino acid sequence conservation with the remaining majority of G-protein coupled receptors (the rhodopsin family). Much less is known about structure-function relationships and effector system coupling of the secretin-VIP family receptors. Their cloning has also raised new questions about their physiological roles and created tools for study of their distribution, regulation and pharmacology. We are currently pursuing the physiological role of the PTH2 receptor which we identified as a novel parathyroid hormone (PTH) activated receptor in a screen of brain cDNA libraries 4 years ago. This receptor is most abundant in the brain but we detect no PTH, its only known ligand, in the CNS. The original functional characterization used the human receptor while the receptors distribution was mapped in the rat. We recently cloned and studied the function of the rat receptor to help reconcile data from these two approaches. The rat PTH2 receptor is poorly activated by PTH, but is potently activated by a substance found in bovine hypothalamic extracts. We have now purified this peptide to homogeneity, determined its amino acid sequence and had it chemically synthesized. It is a potent selective activator of the rat and human PTH2 receptors. We have continued with detailed anatomical mapping of the PTH2 receptor. Recent investigation revealed high levels of expression within terminals of primary sensory neurons in the superficial dorsal horn suggesting that this novel peptide- receptor system may be involved in modulation of nociception. We are currently investigating this possibility and the role of the receptor system in other CNS functions. - neuropeptides, neurotransmitters, receptors, neuroendocrine, purification, anatomy, nociception